In 1931, Whorf began studying linguistics at Yale University and soon deeply impressed Edward Sapir, who warmly supported Whorf's academic pursuits. In 1936, Whorf was appointed Honorary Research Fellow in Anthropology at Yale. In 1937, Yale awarded him the Sterling Fellowship. He was a Lecturer in Anthropology from 1937 through 1938, when he began having serious health problems.

Whorf said that having an independent, non-academic source of income allowed him to pursue his specific academic interests more freely. He disseminated his ideas not only by publishing numerous technical articles, but also by writings accessible to lay readers, and by popular lectures.

Whorf's primary area of interest in linguistics was the study of Native American languages, particularly those of Mesoamerica. He became well known for his work on the Hopi language, and for his principle of linguistic relativity. Among Whorf's beliefs about the Hopi was that: “… the Hopi language is seen to contain no words, grammatical forms, construction or expressions or that refer directly to what we call “time”, or to past, present, or future…”[1]

The Sapir-Whorf hypothesis proposed that language affects thought. Also sometimes called the Whorfian hypothesis, this claims that the language a person speaks affects the way that he or she thinks, meaning that the structure of the language itself affects cognition.

Some of Whorf's early work on linguistics and particularly on linguistic relativity was inspired by reports he wrote on insurance losses, in which misunderstanding based on linguistic confusion had been a contributing factor. In an incident recounted in his essay The Relation of Habitual Thought and Behavior to Language.[2], Whorf explains how the idea of language affecting thought first came to him. Employed as an investigator for a fire insurance company, his job was to investigate the causes of industrial fires. In his own words:

"My analysis was directed toward purely physical conditions, such as defective wiring, presence or lack of air spaces between metal flues and woodwork, etc., and the results were presented in these terms. ... But in due course it became evident that not only a physical situation qua physics, but the meaning of that situation to people, was sometimes a factor, through the behavior of people, in the start of a fire. And this factor of meaning was clearest when it was a LINGUISTIC MEANING [Whorf's emphasis], residing in the name or the linguistic description commonly applied to this situation. Thus, around a storage of what are called 'gasoline drums,' behavior will tend to a certain type, that is, great care will be exercised; while around a storage of what are called 'empty gasoline drums,' it will tend to be different -- careless, with little repression of smoking or of tossing cigarette stubs about. Yet the 'empty' drums are perhaps the more dangerous, since they contain explosive vapor. Physically, the situation is hazardous, but the linguistic analysis according to regular analogy must employ the word 'empty,' which inevitably suggests a lack of hazard. The word 'empty' is used in two linguistic patterns: (1) as a virtual synonym for 'null and void, negative, inert,' (2) applied in analysis of physical situations without regard to, e.g., vapor, liquid vestiges, or stray rubbish, in the container."[2]

In studying the cause of a fire which had started under the conditions just described, Whorf concluded that it was thinking of the "empty" gasoline drums as "empty" in the meaning described in the first definition (1) above, that is as "inert," which led to a fire he investigated. His papers and lectures featured many other examples from his insurance work to support his belief that language shapes understanding.

Less well known, but important, are his contributions to the study of the Nahuatl and Maya languages. He claimed that Nahuatl was an oligosynthetic language (a claim that would be brought up again some twenty years later by Morris Swadesh, another controversial American linguist). In a series of published and unpublished studies in the 1930s, he argued that Mayan writing was phonetic to some degree. Although many details of his work on Maya are now known to have been incorrect, his central claim was vindicated by Yuri Knorozov's syllabic decipherment of Mayan writing in the 1950s.

Whorf died of cancer at the age of 44. He is mainly remembered for a posthumous collection of his work, titled Language, Thought, and Reality, first published in 1956.